A role for viral infection in the aetiology of coeliac disease?

"In this longitudinal study, we found that a higher frequency of enterovirus infections was associated with increased risk of coeliac disease."

So said the findings reported by Christian Kahrs and colleagues [1] (open-access available here) based on the results of their: "Case-control study nested within Norwegian birth cohort recruited between 2001 and 2007 and followed to September 2016."

Following the screening of some 47,000 infants for the 'genetics of coeliac disease' - HLA genotype DR4-DQ8/DR3-DQ2 - over 900 children were entered on to the study. This group were followed "with repeated blood and faecal samples from the age of 3 months" for quite a few years. Just over 500 participants who quite regularly donated blood samples, were asked if they wanted a screen for coeliac disease. Two hundred and twenty of them (or their parents/guardians) said 'yes please' and the study results were drawn from this group. Twenty seven of the 220 participants with those all-important coeliac risk genes were diagnosed with the condition. Twenty five of those 27 diagnosed with coeliac disease were matched against 50 of the no coeliac disease participants; matching was done "for duration of follow-up, date of birth, and county of residence." It was then just a case of looking at all the biological data that had been accrued from those blood and fecal samples to ascertain things like (a) "the time interval when cases seroconverted for coeliac disease markers" (i.e. when the antibodies diagnostic of coeliac disease began to be present) and (b) if and when enterovirus was detected in some of the samples (stool samples) via PCR (polymerase chain reaction).

Results: as shown in the supplementary material, the mean age at first presence of coeliac disease (CD) antibodies in the CD diagnosed sample (n=25) was around 42 months (when the first positive sample was recorded). Symptoms 'debut' was around an average age of 73 months and CD diagnosis was received on average at 87 months. Enterovirus was reported in both CD (n=25) and non-CD groups (n=49). Some 20% of the stool samples from the CD group were positive for some kind of enterovirus exposure compared with 16% of controls. Slightly more enterovirus positive stool samples were observed in the CD group (median 4 positive samples per child) than the control group (median 3 positive samples per child).

As per the opening quote to this post: "Enterovirus was found in 370 (17%) of 2135 samples and was significantly more frequent in samples collected before development of coeliac disease antibodies in cases than in controls." Further: "The association was restricted to infections after introduction of gluten." In other words, there seemed to be some evidence of a possible temporal connection between enterovirus and the development of CD, suggesting that enterovirus exposure and not gluten was the more important trigger for CD.

Mechanisms? Well, there's some speculation about that in the Kahrs paper and a: "plausible explanation is that enterovirus causes impaired barrier function, which in turn increases the risk of coeliac disease." Enterovirus causing impaired intestinal (gut) barrier function eh? Interesting, does that mean 'leaky gut' might have a viral origin in some cases? Mmm, that could have lots of implications...

Obviously more investigation is required in this area. The Kahrs study has some strengths in terms of the sample collection protocols and frequency and potentially establishing a temporal *link* between CD and enterovirus exposure. But there's still more to do: "unmeasured confounding factors or residual confounding can never be entirely ruled out in non-randomised studies." But don't let that take anything away from the potential importance of these findings.

And on the topic of prospectively following children who might be prone to develop coeliac disease, the study findings published by Lionetti and colleagues [2] are equally interesting. In particular, based on 23 of their 26 children who received a "potential diagnosis of CD" but nonetheless "continued a gluten-containing diet... 19 (83%) became antibodies negative at 1 year from the first biopsy and remained negative up to 10 years of follow-up." Could there be a tie-up with the Kahrs findings perhaps?

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[1] Kahrs CR. et al. Enterovirus as trigger of coeliac disease: nested case-control study within prospective birth cohort. BMJ. 2019 Feb 13;364:l231.

[2] Lionetti E. et al. Long-Term Outcome of Potential Celiac Disease in Genetically at-Risk Children: The Prospective CELIPREV Cohort Study. J Clin Med. 2019 Feb 5;8(2). pii: E186.

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Borna disease virus antibodies and autism: baseline data setting the scene

The findings reported by Tomoyuki Honda and colleagues [1] setting out a baseline prevalence rate of antibodies against bornavirus in children diagnosed with an autism spectrum disorder (ASD) provides the blogging fodder today. Whilst the Honda findings might not exactly sound like 'exciting science' I would perhaps beg to differ...

Although no expert on Borna disease or Borna disease virus (BDV), I am an interested amateur. Borna disease was named after the town of Borna in Germany, where a fatal neurological (encephalitic) disease affected certain livestock including sheep, cattle and horses. The causative agent was found to be BDV. As well as being characterised by a "meningoencephalomyelitis" state, the symptoms of Borna disease also stretch to certain behaviours. This includes stereotypical behaviours (animals travelling in circular movements or standing in peculiar positions and poses) as well as ataxia affecting coordination and balance. Presentation in some animals has led to the name 'Staggering disease' being used.

Although predominantly seen as a disease affecting animals and livestock, there has been a gradual shift towards the idea that Borna disease virus can also infect humans too. Quite a lot of scientific resources have, for example, concluded that BDV might show an important connection to human psychiatric diagnoses/conditions such as schizophrenia [2]. This, on the basis of serological evidence for recent or continued viral exposure. Following on from a previous case report from Honda and colleagues [3] describing antibodies against BDV in a child with autism and her mother, the authors seem to have developed an interest in all-things BDV and autism. There has also been discussion about a BDV rodent model of autism from other research groups [4] including from the now [sadly] non-functioning research tag-team that was Hornig and Lipkin [5].

On this latest research occasion, Honda et al observed a few things. First: "The prevalence of antibodies against bornavirus-specific speckles, N, and P proteins were 22%, 48%, and 33%, respectively, in the ASD children." For discussions on 'Bornavirus-specific speckles, N, and P proteins' I'll refer you to some other work including Honda on the authorship title [6] on the viral nitty-gritty details. Second: "According to our criteria, the prevalence of antibodies against bornaviruses was 7.4% in the ASD children." Bearing in mind a dearth of investigations on the estimated prevalence of Borna virus more generally, particularly in children, and the various ways and means that immunological contact with the virus can be assayed by, that percentage did seem quite high. Other work [6] for example, has talked about a figure of 2% 'exposure' rate in non-clinical populations. I suppose the 'baseline data' from Honda is trying to make in-roads into this prevalence issue.

Obviously, there's a way to go yet on this topic before any sweeping generalisations are made. The impact of viral infection/illness in relation to [some] autism has quite a long peer-reviewed research history; be that the effect of congenital cytomegalovirus (CMV) (see here) or the work looking at rubella and autism (see here) for examples. The more contemporary research base examining various encephalitis conditions also presenting as autism or autistic-like disorder(s) (see here and see here) is also important. With regards to any specific possible connection between Borna disease virus and autism, future work needs to establish lots of things (infection route, exposure characteristics, etc.). We also need to know whether behavioural symptoms/traits are actually 'caused' by such viral exposure or perhaps more generally linked to immune responses as per the whole 'immune system does more than just fight infection' bit. If a link is shown beyond reasonable doubt, there could be some real scientific advances possibilities on the back of what is already emerging [7]. But at the moment, it's still 'a big if'...

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[1] Honda T. et al. Prevalence of antibodies against Borna disease virus proteins in Japanese children with autism spectrum disorder. Microbiol Immunol. 2018 May 22.

[2] Azami M. et al. The association between Borna Disease Virus and schizophrenia: A systematic review and meta-analysis. Asian J Psychiatr. 2018 Apr;34:67-73.

[3] Honda T. et al. Detection of Antibodies against Borna Disease Virus Proteins in an Autistic Child and Her Mother. Jpn J Infect Dis. 2017;70(5):599.

[4] Pletnikov MV. et al. Developmental brain injury associated with abnormal play behavior in neonatally Borna disease virus-infected Lewis rats: a model of autism. Behav Brain Res. 1999 Apr;100(1-2):43-50.

[5] Hornig M. et al. An infection-based model of neurodevelopmental damage. Proc Natl Acad Sci U S A. 1999 Oct 12;96(21):12102-7.

[6] Matsumoto Y. et al. Bornavirus Closely Associates and Segregates with Host Chromosomes to Ensure Persistent Intranuclear Infection. Cell Host & Microbe. 2012; 11: 492-503.

[7] Honda T. et al. Neuropathogenesis of persistent infection with Borna disease virus. Uirusu. 2015;65(1):145-54.

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Congenital cytomegalovirus (CMV) infection and autism continued and meta-analysed

The findings - based on systematic review and meta-analysis - reported by Kaori Maeyama and colleagues [1] make for important reading on the topic of an "association of congenital cytomegalovirus (CMV) infection with autism spectral disorder (ASD)." CMV by the way, is a herpesvirus that can be potentially transmitted during pregnancy from mother to developing child and can, in some instances, lead to various adverse developmental and neurodevelopmental outcomes.

I've talked about CMV and autism a few times already on this blog (see here and see here) including the idea that, outside of any possible *link* with some autism, there may [eventually] be ways and means of protecting against some of the adverse effects of such viral exposure during such a critical period (see here) (with lots more research required).

Maeyama et al concluded that a "high prevalence of congenital CMV infection in ASD cases (OR 11.31, 95% CI 3.07-41.66) was indicated" on the basis of their analysis of the collected research literature published so far. They caution however, that quite a bit more research is required. Not least on how much of a contribution CMV infection might make to the very broad autism spectrum.

As I've said before on this topic, the data so far produced suggest that 'CMV-related autism' (if I can call it that) is likely to be quite a rare occurrence but we don't know for sure. Part of that stems from the fact that I don't think CMV is routinely screened for during pregnancy (at least here in Blighty) and I'm pretty sure that most autism assessments/diagnostic procedures probably won't also ask about or include a screen for CMV exposure either. It's therefore highly likely that we don't yet know the true extent to which CMV infection may/may not be linked to autism.

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[1] Maeyama K. et al. Congenital Cytomegalovirus Infection in Children with Autism Spectrum Disorder: Systematic Review and Meta-Analysis. J Autism Dev Disord. 2017 Nov 28.

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On preventing the deleterious effects of CMV: implications for some autism?

"Anxiety drug may prevent common virus that causes birth defects" went one of the headlines covering the study results published by Sara Ornaghi and colleagues [1].

Continuing a research theme from this group (see here) on how use of some mood stabilising medicines at critical periods might have some important impact on the deleterious effects of cytomegalovirus (CMV) infection, there is quiet optimism that this new research could have big implications for a range of different labels including some autism (see here).

So: "Valnoctamide (VCD), a neuroactive mood stabilizer with no known teratogenic activity, was recently demonstrated to have anti-CMV potential" was the starting premise for the Ornaghi study. Using mouse models - that's MOUSE models - of CMV infection and whether the anti-CMV potential of VCD could be "translated into an efficacious therapeutic effect to improve CMV-induced adverse neurological outcomes", researchers first looked at survival rates when injected 'low-dose' VCD was used. They reported that compared with those receiving a control substance (not VCD), the mice in receipt of VCD were more likely to survive. As per the media chatter about this study: "They lived longer, their body weight was greater – everything about them looked better" on the basis that congenital CMV infection can, in some cases, prove fatal.

Researchers also assessed whether various 'adverse neurological outcomes' associated with congenital CMV infection might be potentially offset by the use of VCD. They observed that: "VCD during the first 3 weeks of life restored timely acquisition of neurological milestones in neonatal male and female mice and rescued long-term motor and behavioral outcomes in juvenile male mice."

Then to the possible mechanism of effect, and based on the use of "CMV-infected human fetal astrocytes" they observed that "VCD reduced both viral infectivity and replication by blocking viral particle attachment to the cell." In other words, VCD, a medicine typically indicated as a sedative, seemed to possess some quite potent activity in relation to how CMV takes hold in important cells in the brain.

I've already mentioned about how at least some cases of autism might benefit from this work. I say this on the basis that there is a robust evidence base suggesting that congenital CMV infection could very well result in autism (see here). There is a need for quite a bit more investigation in this area in terms of translating mouse findings into human findings (see here) but the promises of this area of work are not to be under-estimated...

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[1] Ornaghi S. et al. Valnoctamide inhibits cytomegalovirus infection in developing brain and attenuates neurobehavioral dysfunctions and brain abnormalities. J Neurosci. 2017. June 19.

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HSV-2 gestational infection and offspring autism risk

"In our cohort, high levels of antibodies to herpes simplex virus 2 at midpregnancy were associated with an elevated risk of autism spectrum disorder in male offspring. These findings provide support for the hypothesis that gestational infection may contribute to the pathogenesis of autism spectrum disorder and have the potential to drive new efforts to monitor women more closely for cryptic gestational infection and to implement suppressive therapy during pregnancy."

That was the conclusion reached in the paper published by Milada Mahic and colleagues [1] including the research tag-team that is Mady Hornig and Ian 'virus hunter' Lipkin in the list of contributing authors. Having already received some media attention (see here), it doesn't need much more from me but I do want to include a few details and relevant points in this blog entry.

So, the Autism Birth Cohort was the starting point, and "442 mothers of children with ASD... and 464 frequency-matched controls" who all provided plasma samples "(903 samples acquired at midpregnancy and 878 acquired after delivery)." Said samples were analysed for IgG antibodies to ToRCH agents: "Toxoplasma gondii, rubella virus, cytomegalovirus (CMV), and herpes simplex viruses 1 (HSV-1) and 2 (HSV-2)." Some of those viruses and parasites have previously been mentioned with [some] autism in mind (see here and see here and see here).

Results: well, an important detail first: "Because rubella vaccination is part of the routine child vaccination schedule in Norway, almost all individuals had IgG antibodies to rubella virus." Indeed, other authors have speculated that rubella vaccination has actually "prevented substantial numbers" of autism as a knock-on effect of reducing the numbers of cases of congenital rubella syndrome [2]. Vaccination doing more than just saving lives eh?

Next: "Our data suggest that the presence of high levels of anti-HSV-2 antibodies at midpregnancy increases the risk of ASD [autism spectrum disorder] in boys." The authors complemented this finding by some rather neat statistical wizardry whereby odds ratios were calculated based on "four different anti-HSV-2 reference levels (60, 120, 180, and 240 arbitrary units [AU]/ml)." Having said that: "High levels of antibodies, which are typically indicative of recent infection, were found in only a small number of subjects." They also reported "no statistically significant association with risk was found with high levels of HSV-2 antibodies at delivery" and saw nothing significant when it came to the other infections examined. These important points have been picked up in the NHS Choices entry on this study (see here).

These are interesting findings and, as far as I can see, represent something quite novel to the quite vast autism research landscape (assuming you count maternal HSV-2 levels and not antibody levels in actual people diagnosed with autism). The reliance on data from an initiative like the Autism Birth Cohort ensured some rigour in terms of the diagnosis of autism [3] and with the reputations following Drs Hornig and Lipkin, one would have to be pretty brave to question their virus-hunting credentials also with autism in mind [4].

Then to the million-dollar question: how might elevated HSV-2 antibodies during pregnancy affect offspring risk of autism? There is a familiar theme offered by the authors to this question as per statements like: "ASD risk associated with high levels of antibodies to HSV-2 is not specific to HSV-2 but instead reflects the impact of immune activation and inflammation on a vulnerable developing nervous system." I know some people still have a bit of a problem with the idea that something like maternal immune activation (MIA) might up the risk for various offspring outcomes [hint: if an article contains the word 'truth' in the title, step away] but please, stop with the 'it can never happen' generalisations and instead look to the existing peer-reviewed evidence on the topic [5]. Yes, science needs to do more on the topic of MIA and autism but clues are emerging all the time...

Oh, and I'll be coming to research talking about another member of the herpesviruses in relation to autism quite soon on this blog.

To close, operation hardtack and other videos (best viewed in full-screen mode).

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[1] Mahic M. et al. Maternal Immunoreactivity to Herpes Simplex Virus 2 and Risk of Autism Spectrum Disorder in Male Offspring. mSphere. 2017. Feb 22.

[2] Berger BE. et al. Congenital rubella syndrome and autism spectrum disorder prevented by rubella vaccination - United States, 2001-2010. BMC Public Health. 2011; 11: 340.

[3] Stoltenberg C. et al. The Autism Birth Cohort (ABC): A Paradigm For Gene-Environment-Timing Research. Molecular Psychiatry. 2010;15(7):676-680.

[4] Hornig M. et al. Lack of association between measles virus vaccine and autism with enteropathy: a case-control study. PLoS One. 2008 Sep 4;3(9):e3140.

[5] Careaga M. et al.  Maternal Immune Activation and Autism Spectrum Disorder: From Rodents to Nonhuman and Human Primates. Biol Psychiatry. 2017 Mar 1;81(5):391-401.

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Milada Mahic, Siri Mjaaland, Hege Marie Bøvelstad, Nina Gunnes, Ezra Susser, Michaeline Bresnahan, Anne-Siri Øyen, Bruce Levin, Xiaoyu Che, Deborah Hirtz, Ted Reichborn-Kjennerud, Synnve Schjølberg, Christine Roth, Per Magnus, Camilla Stoltenberg, Pål Surén, Mady Hornig, & W. Ian Lipkin (2017). Maternal Immunoreactivity to Herpes Simplex Virus 2 and Risk of Autism Spectrum Disorder in Male Offspring. mSphere : 10.1128/mSphere.00016-17

Establishing environmental exposures as risk factors for bipolar disorder: Difficult.

The findings reported by Ciro Marangoni and colleagues [1] made for some interesting reading recently and their systematic review of longitudinal studies looking at the various environmental exposures put forward as possible risk factors pertinent to the development of bipolar disorder (BD).

Trawling through the peer-reviewed material on this topic, the authors were able to 'clump' the various proposed risk factors into one of three categories: "neurodevelopment (maternal influenza during pregnancy; indicators of fetal development), substances (cannabis, cocaine, other drugs - opioids, tranquilizers, stimulants, sedatives), physical/psychological stress (parental loss, adversities, abuses, brain injury)."

They did not however, report the presence of any specific 'smoking gun' on the basis of their investigations, concluding that: "Only preliminary evidence exists that exposure to viral infection, substances or trauma increase the likelihood of BD." That also the various risk categories seemed to be 'correlated' with various other psychiatric and/or behavioural labels is also an important point to make in these days of overlap and RDoC.

I personally am not surprised by these results. Appreciating that diagnostic labels do not equal homogeneous groups, and that just as when defining the genetics of something like BD, so defining the non-genetic correlates is an equally difficult task, studies of this type remind us just how complicated and individual the paths are bringing someone to such a clinically-relevant label. I say this with the understanding that just because an specific environmental (or non-environmental) risk factor might not be generalisable to all BD does not mean it can't exert a more pronounced effect in smaller groups or individuals. Lessons from other labels teach us this (see here).

Whilst important to understand whether there may be specific environmental exposures that might be more generally linked to an enhanced risk of developing BD, I do believe that the [research] future lies in a couple of other areas looking at: (a) how many different types of BD are there and what are the 'other' conditions/labels potentially related? (b) what does the biology of BD look like and does it include some common targets with other labels? and (c) outside of the array of interventions put forward for managing symptoms (see here), are there other intervention strategies that might fit with the findings of (a) and (b)?

To close, LEGO do it best...

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[1] Marangoni C. et al. The role of environmental exposures as risk factors for bipolar disorder: A systematic review of longitudinal studies. J Affect Disord. 2016 Jan 1;193:165-174.

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Marangoni C, Hernandez M, & Faedda GL (2016). The role of environmental exposures as risk factors for bipolar disorder: A systematic review of longitudinal studies. Journal of affective disorders, 193, 165-174 PMID: 26773919

Psychiatric history + infection during pregnancy increases the risk of psychosis in offspring

The title of this (hopefully) brief post mirrors the conclusion reached by Åsa Blomström and colleagues [1] who analysed data pertinent to all children "born in Sweden 1978-1997" to calculate hazard ratios (HRs) of nonaffective psychosis "in relation to maternal infection during pregnancy." Also detailing RERI - relative excess risk due to interaction - bringing in factors such as maternal history of psychiatric disorder as part and parcel of any effect, and authors reported that: "Among mothers with a history of psychiatric disease, infection during pregnancy increases the risk of psychosis in offspring." The authors further speculate that: "Maternal infections during pregnancy appear to contribute to the risk of childhood infections, which together render the child more vulnerable to psychosis development."

I've covered research on the potential effects of maternal infection during pregnancy for offspring child and adult outcomes before on this blog (see here for example). Names like Alan Brown and the late Paul Patterson have done much to put some scientific flesh on the bones of this hypothesis particularly with schizophrenia in mind [2].

The Blomström findings add a new layer to the idea of a connection between viral exposure, immune function during pregnancy and 'programming' for offspring psychiatric risk insofar as the idea that elements of familial psychiatric history might also play something of a synergistic role in this relationship. You might well say that parental psychiatric history already puts offspring at greater risk and perhaps represents the larger factor here. Bear in mind however the observation that maternal infection correlated with childhood infection and that this might also play a hand in the development of psychosis and one could speculate that the genetics of psychiatric illness might also overlay with the genetics of infection susceptibility for example. Add in the idea that immune function seems to be more readily accepted as a feature of psychiatric presentation [3] alongside the concept of inflammation being potentially relevant (see here) and voilà, lots of ideas for further study.

Music: Sigma ft. Ella Henderson - Glitterball.

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[1] Blomström Å. et al. Associations Between Maternal Infection During Pregnancy, Childhood Infections and the Risk of Subsequent Psychotic Disorder-A Swedish Cohort Study of Nearly 2 Million Individuals. Schizophr Bull. 2015 Aug 24. pii: sbv112.

[2] Brown AS. & Patterson PH. Maternal Infection and Schizophrenia: Implications for Prevention. Schizophrenia Bulletin. 2011;37(2):284-290.

[3] Gibney SM. & Drexhage HA. Evidence for a dysregulated immune system in the etiology of psychiatric disorders. J Neuroimmune Pharmacol. 2013 Sep;8(4):900-20.

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Blomström Å, Karlsson H, Gardner R, Jörgensen L, Magnusson C, & Dalman C (2015). Associations Between Maternal Infection During Pregnancy, Childhood Infections and the Risk of Subsequent Psychotic Disorder-A Swedish Cohort Study of Nearly 2 Million Individuals. Schizophrenia bulletin PMID: 26303935

A viral 'cause' of obesity?

I must thank Leah Hardy (@LeahFHardy) for bringing to my attention the paper by Qinglong Shang and colleagues [1] (open-access available here) reporting that: "Ad36 [Human adenovirus 36] infection is associated with an increased risk of obesity development."

Based on a meta-analysis of the available research literature examining whether Ad-36 - "a nonenveloped icosahedral virus comprised of double-stranded DNA and is one of 56 serotypes in 7 subgroups of human adenoviruses" - might be linked to obesity, researchers concluded that the weight of evidence from 11 studies did favour "an association between Ad36 infection and a significantly increased risk of obesity development, especially in children." Such findings can be added to other meta-analyses [2] that have also previously suggested that there may be more to see in this 'infectobesity' area [3].

I have to say that I was quite unaware of the links being made between Ad-36 and obesity prior to reading the Shang paper. I've previously tackled the idea that the obesity might have some important microbiological links (see here) before on this blog but never considered the possibility of a viral infection as showing involvement until now. Obviously one has to be a little guarded against making any sweeping statements that for example, Ad-36 is the primary cause of all obesity, because in all likelihood the issue is likely to be rather more complex than that. Appreciating that the old 'energy in, energy out' hypothesis is itself likely to be an over-simplification of why we are faced with growing rates of overweight and obesity, I'm sure that Ad-36 probably fits into a rather large jigsaw puzzle - somewhere. The requirement for a greater understanding of the hows and whys of any viral - obesity link is also strong alongside the idea that even if proved, any viral link should not absolve responsibility for eating and exercising right as part of maintaining a healthy weight.

Research such as that from Berger and colleagues [4] suggesting that "Ad36(+) may be associated with biomarkers implicated in inflammation but not with greater levels of fat mass" offers some cautionary data on why there may be quite a bit more research needed looking at Ad-36 and obesity. If one considers that inflammation seems to be part and parcel of obesity, the whole thing starts to get quite a bit more complicated.

Still, if science does start to get closer to the idea that Ad-36 (or other agents) might indeed heightened the risk of obesity and perhaps even suggest 'transferability' from person-to-person, this may open up new ways of tackling this issue [5] even with the prospect of immunising against infection-induced weight gain [6].

Music: Babies by Pulp.

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[1] Shang Q. et al. Serological data analyses show that adenovirus 36 infection is associated with obesity: a meta-analysis involving 5739 subjects. Obesity (Silver Spring). 2014 Mar;22(3):895-900.

[2] Yamada T. et al. Association of Adenovirus 36 Infection with Obesity and Metabolic Markers in Humans: A Meta-Analysis of Observational Studies. PLoS One. 2012; 7(7): e42031.

[3] Valiquette L. et al. A microbiological explanation for the obesity pandemic? Can J Infect Dis Med Microbiol. 2014 Nov-Dec;25(6):294-5.

[4] Berger PK. et al. Association of adenovirus 36 infection with adiposity and inflammatory-related markers in children. J Clin Endocrinol Metab. 2014 Sep;99(9):3240-6.

[5] Esposito S. et al. Adenovirus 36 infection and obesity. J Clin Virol. 2012 Oct;55(2):95-100.

[6] Na HN. & Nam JH. Proof-of-concept for a virus-induced obesity vaccine; vaccination against the obesity agent adenovirus 36. Int J Obes (Lond). 2014 Nov;38(11):1470-4.

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Shang Q, Wang H, Song Y, Wei L, Lavebratt C, Zhang F, & Gu H (2014). Serological data analyses show that adenovirus 36 infection is associated with obesity: a meta-analysis involving 5739 subjects. Obesity (Silver Spring, Md.), 22 (3), 895-900 PMID: 23804409